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Key words: epigenetic, DNA methylation, histone acetylation, autocrine, prostate cancer
Abstract
Epigenetic mechanisms may be the main driving force for critical changes in gene expression that are responsible for progression of prostate cancers. The three most extensively characterized mechanisms for epigenetic generegulation are (i) changing patterns ofDNAmethylation, (ii) histone acetylations/deacetylations, and (iii) alterations in regulatory feedback loops for growth factors. Several studies have indicated that DNA hypermethylation is an important mechanism in prostate cancer for inactivation of key regulatory genes such as E-cadherin, pi-class glutathione S-transferase, the tumor suppressors CDKN2 and PTEN, and IGF-II. Similarly, histone acetylations and deacetylations are frequently associated respectively with transcriptional activation (e.g. IGFBP-2 and p21) and repression (e.g. Mad:Max dimers) of genes linked to prostate cancer progression. Recently, histone acetyltransferase and deacetylase activities have been shown to be intrinsic with transcriptional coregulator proteins that bind to steroid receptors (e.g. SRC-1 and PCAF). Changes in regulatory feedback loops for growth factors with prostate cancer progression tend toward shifts from paracrine to autocrine control where the receptor and ligand are produced by the same cell. While there are several examples of this progression pattern in prostate tumors such as with IGF, FGF, TGF-- and their respective receptors, the precise mechanism (i.e. epigenetic or mutational) is less certain. In the context of treatment options, the contribution of mutational versus epigenetic events to prostate cancer progression is an improtant consideration. Irreversible genetic changes are likely to be less amenable to therapeutic control than are epigenetic ones.
1. Introduction
Cancer progression is generally thought of as a series of changes in the malignant cell whereby its appearance and behavior inexorably evolve towards a more aggressive and poorly differentiated phenotype. With prostate cancer, the term progression is often used in an endocrine sense to connote the process in which there is a change in hormone dependency from androgen dependence to androgen independence. In either case, these changes are usually credited to irreversible chromosomal rearrangements, losses and duplications or gene mutations inherent to tumorigenesis. However, at present there is very little direct proof to support mutation as the primary cause of progression of prostate cancers. Rather, the evidence available would suggest that changes in gene expression, particularly those which arise through an epigenetic or adaptive mechanism,...